complex disorders, genetic heterogeneity

identifying genetic red flags

-family history of a known or suspected genetic condition -multiple affected family members with the same or related disorders -earlier age at onset of disease then expected -developmental delays or mental retardation -diagnosis in less affected sex (breast cancer in males) -multifocal or bilateral occurrence in paired organs -blood relationship of parents (consanguinity) -ethnic predisposition to certain genetic disorders -one or major malformations -abnormalities in grows -recurrent pregnancy losses (2+) -disease in the absence of risk factors

multifactorial inheritance

-interaction of one or more genes with environmental factors. has a familial nature and an environmental dependence -most normal phenotypic differences among individuals are due to this (differences in heigh, hair and skin color, intelligence)

clinical characteristics of complex disorders

-most common type of disorders seen in practice -tends to be familial, but there is no distinctive pattern of inheritance within a single family -frequency of disease in second degree relatives is much lower than in first degree relatives -the concordance rate in monozygotic twins is significantly greater than in dizygotic twins -common among children of consanguineous parents -tend to occur more frequently in one sex than the other -recurrence risk is proportional to the number of family members who already have the disease -recurrence risk is proportional to the severity of the condition in the proband -recurrence risk is the same for all relatives who share the same proportion of genes-recurrence risk is higher for relatives of the less susceptible sex -the theoretical risk of first-degree relatives is approximately the square root of the population incidence (I^(1/2) -if underlying genetic mechanism is not know the empiric risk is used instead

what are the two types of genetic heterogeneity

1) locus or non allelic heterogeneity 2) allelic heterogeneity

type 2 diabetes mellitus (T2DM)

10 times more prevalent 95% of patients strong genetic basis multifactorial

Type 1 diabetes mellitus (T1DM)

5-10% genetic basis multifactorial two loci IDDM1 and IDDM2 account for genetic predisposition

What are the most common types of disorders seen in practice?

complex multifactorial disorders

allelic heterogeneity

production of similar phenotypes by different mutant alleles at a single locus. found for most genetic diseases

locus or non allelic heterogeneity

the production of similar phenotypes by mutations at different genetic loci. the rule in multifactorial diseases

genetic heterogeneity

the production of the same phenotype by more than one genotype

polygenic traits

traits generated by the combined action of many genes